Management of nodular lymphocyte-predominant Hodgkin lymphoma: recommendations and unresolved dilemmas
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Acta Haematologica Polonica 2021
Number 4, Volume 52, pages 314–319
DOI: 10.5603/AHP.2021.0060 REVIEW ARTICLE
ISSN 0001–5814
e-ISSN 2300–7117
Management of nodular lymphocyte-predominant
Hodgkin lymphoma:
recommendations and unresolved dilemmas
Ewa Paszkiewicz-Kozik
Department of Lymphoid Malignancies, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
Abstract
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare malignancy of young adults characterized by an
indolent and recurrent course. Although relapses or transformation to aggressive B cell lymphoma can occur decades
after the primary diagnosis, the prognosis of NLPHL is relatively good, with as much as a 90% 10-year overall survival
rate. The rarity of NLPHL makes it difficult to conduct multicenter prospective studies to establish separate guidelines
for the diagnosis and treatment of this disease.
Therefore, the recommendations for the treatment of NLPHL have for many years been the same as for classic Hodgkin
lymphoma, except for early stages without risk factors. The registration of anti-CD20 monoclonal antibody for the treat-
ment of CD20-positive B-cell lymphomas has opened up new perspectives for NLPHL patients. Modern and accurate
histopathological examinations as well as imaging diagnostics, especially positron emission tomography/computed
tomography has allowed a more precise distinction to be made between the indolent NLPHL and the transforming-to-ag-
gressive lymphoma forms. This review is intended to provide readers with the clinical features, course, outcome and
methods of standard treatment in patients with NLPHL. The author in particular wishes to draw attention to unresolved
issues regarding standard management and also the use of active surveillance, anti-CD20 immunotherapy, less aggres-
sive regimens of chemotherapy, and indications for new treatment options.
Key words: NLPHL, radiotherapy, immunochemotherapy, new agents
Acta Haematologica Polonica 2021; 52, 4: 314–319
Introduction treatment initiation (i.e. whether within 12 months of
diagnosis) [1]. Unlike cHL, NLPHL relapses can occur many
Nodular lymphocyte-predominant Hodgkin lymphoma years after initial or subsequent lines of therapy. NLPHL is
(NLPHL) accounts for 5% of Hodgkin lymphoma (HL). In a rare neoplasm, with a crude incidence in Europe of 2.3
contrast to classic Hodgkin lymphoma (cHL), it is char- per 100,000 per year [2]. In 2018, 659 cases of HL were
acterized by an indolent and recurrent course. Although registered to the Polish National Cancer Registry. This
late relapses and transformation to diffuse large B cell corresponds to up to 30 new cases per year of NLPHL in
lymphoma (DLBCL) can occur, NLPHL prognosis is rela- Poland [3]. Adequate surgical biopsy of lymph node for
tively good. Based on long term data from multicenter formalin-fixed sample is required for a diagnosis of NLPHL.
registries, 10-year overall survival is 57–99% depend- In the histological examination malignant cells termed
ing on the clinical stage of the disease and the time of lymphocyte-predominant cells (LP cells, popcorn cells)
Address for correspondence: Ewa Paszkiewicz-Kozik, Department Copyright © 2021
of Lymphoid Malignancies, Maria Skłodowska-Curie National Research The Polish Society of Haematologists and Transfusiologists,
Institute of Oncology, Roentgena 5, 02–781 Warsaw, Poland, Insitute of Haematology and Transfusion Medicine.
e-mail: Ewa.Paszkiewicz-Kozik@pib-nio.pl All rights reserved.
Received: 10.05.2021 Accepted: 27.05.2021
This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to down-
load articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.
314 www.journals.viamedica.pl/acta_haematologica_polonicaEwa Paszkiewicz-Kozik, NLPH: recommendations and unresolved dilemmas
are located in the background of small B lymphocytes, according to EORTC/LYSA and German Hodgkin Study Group
rosetting PD1+ T-cells, epithelioid histiocytes, and follicular (GHSG) scales [2]. Additionally, the German Study Group
dendritic cells. LP cells are germinal centers of origin with has proposed a prognostic scale including three adverse
B cell markers expression (positive for CD20, CD45, CD79a, risk factors: male gender (2 points); low serum albumin
PAX5, OCT2, BOB1, BCL6; negative for CD15 and CD30). level (1 point); and variant growth pattern C–F (1 point).
According to the 2016 revision of the World Health Or- Patients are divided into three risk groups: low (0–1 point);
ganization Classification of Tumors of Hematopoietic and intermediate (2 points); and high (3–4 points) with esti-
Lymphoid Tissues, the variant of growth pattern should be mated 5-year PFSs of 95%, 88% and 69% respectively. The
noted in the diagnostic report: 75% of NLPHL cases show histopathology growth pattern is an independent prognostic
typical nodular growth pattern (classical B-cell rich nodular: factor of progression or relapse, but it has not influenced
A or serpiginous: B), but 25% present different histology pat- the choice of NLPHL treatment thus far. The same applies
terns (C, D, E, or F) with diffuse infiltrates or nodules dom- to other points of the scale [5]. Also, age above 45 years at
inated by surrounding T-cells. Cases of typical histological presentation, advanced stage, low hemoglobin level, and
growth patterns demonstrate localized disease and a better systemic symptoms are considered adverse factors in terms
prognosis in terms of increased response rate and progres- of overall survival (OS) [6, 8]. The risk of transformation to
sion-free survival (PFS) compared to variant histology pat- aggressive B cell lymphoma is approximately 7% in 10 years
terns. NLPHL of variant histology has to be carefully distin- of observation, and 31% in 20 years of NLPHL follow up. The
guished from aggressive B-cell T cell-rich lymphoma [4, 5]. risk is higher in bulky disease and splenic involvement [8].
NLPHL is typically recognized in children and young In everyday clinical practice, the type of therapy for
males aged 30–40. Approximately 75% of cases are lim- newly diagnosed NLPHL is stratified according to disease
ited according to Ann Arbor stage I/II with lymph nodes stage and risk factors. Three groups are distinguished:
involvement. Mediastinal, extranodal, bulky disease or non-bulky (Acta Haematologica Polonica 2021, vol. 52, no. 4
chemotherapy with anti-CD20 antibody RCHOP [10] or in the standard treatment for early favorable NLPHL. Several
some selected cases RCVP [15] or R bendamustine [16]; reports show that the addition of chemotherapy or other
these issues are discussed later. Immunochemotherapy variants of induction strategy in early favorable stages do
lasting 3–4 months with or without radiotherapy can be not improve patient outcomes [12, 19–22]. For instance:
considered in early stages; longer treatment should be ap- in a multicenter retrospective database of stage I/II NLPHL
plied in advanced stages. According to the NCCN guidelines, diagnoses over a 20-year period, the outcome of 559
observation is advised for advanced NLPHL asymptomatic patients was analyzed. Patients underwent radiotherapy,
patients after making individual decisions. chemotherapy, combined modality treatment (radiotherapy
with chemotherapy), observation after surgical excision,
Transformed NLPHL rituximab and radiotherapy or as a single agent. 5-year PFS
In a case of upfront transformation, RCHOP is recom- was 87.1% in the entire group, and 5-year OS was 98.3%.
mended with efficiency comparable to induction strategy 5-year PFS for different kinds of induction strategies were:
for DLBCL [13]. 91.1% in the radiotherapy group; 90.5% after chemotherapy
with radiotherapy; 77.8% after chemotherapy; 73.5% in the
Evaluation of response after first-line observation group; 80.8% after rituximab with radiotherapy;
treatment and 38.5% after rituximab alone [23].
According to the Cheson criteria, PET/CT should be incorpo- For selected groups of patients, total surgical resec-
rated in the staging and assessment of efficacy of induction tion followed by a careful watch-and-wait strategy (active
therapy. If radiotherapy was planned, contrast-enhanced surveillance) is reasonable. This kind of management is
CT is mandatory in the staging period. The re-biopsy of purposely chosen in pediatric and young adult groups to
suspected NLPHL sites should be obtained in cases of sta- avoid potential acute and long-term toxicity e.g. matura-
ble or progressed disease after initial treatment. Also, the tion disorders or secondary malignances. In 163 consec-
verification of recurrence by histopathological examination utive patients, 37 (23%) were observed. 23 of them were
is essential to exclude transformation to aggressive cHL in in early stage, and 14 advanced. 5-year PFS was 77% after
further course of the disease. active surveillance and 87% in the group receiving active
treatment, with no difference in OS. With a median follow
Recommendations: relapsed NLPHL up of 69 months, only 10 patients in the watch-and-wait
group required active treatment [24]. Also, in a French
The initiation of salvage therapy must be preceded by the multicenter study of 164 adult patients, OS did not dif-
histopathological verification of NLPHL recurrence. To pre- fer between the group actively treated or observed. With
cisely describe the clinical stage of the relapsed disease, a median relapse rate of 3 years, 50% of observed pa-
contrast-enhanced CT of the neck, chest and abdomen tients remained without treatment, and with inferior PFS.
with pelvis, or PET/CT, is recommended. OS was equal in both groups [13]. In a prospective pedi-
In localized relapses, radiotherapy can be used. Also, atric trial (NCT00107198), patients younger than 22 with
monotherapy with rituximab can be considered [17]. Salvage stage IA completely resected were observed carefully. In
systemic therapy has to be chosen individually, according to a case of relapse, 3 cycles of doxorubicin, vincristine, cy-
several factors: patient performance status, extent of disease clophosphamide and prednisone were administered. Of
relapse, disease symptoms, and type of previous treatment 52 patients after complete surgical excision, 13 relapsed
[18]. The optimal chemotherapy regimen used for the sec- at a median of 11.5 months. 5-year OS was 100% [19].
ond line in NLPHL is not defined. The implementation of an- Upfront monotherapy with rituximab alone is associated
ti-CD20 monoclonal antibody is essential for cases with no with high response and relapse rates [12, 23]. In the pro-
previous anti-CD20 exposure and if relapse is more than six spective GHSG study, 28 patients with stage IA received
months after prior anti-CD20 therapy. The role of autologous 4 weekly doses of rituximab with an objective response
transplant (AHCT) in not clearly defined in recommendations, rate (ORR) of 100% (85% CR) but 3-year PFS was 81.4%
but it remains a PET/CT guided therapeutic option, the same [25]. In another prospective phase II trial, 39 patients
as in cHL [9]. Patients with transformation to DLBCL should with recurrent or newly diagnosed NLPHL were treated
be managed according to recommendations for relapsed/re- with 4 weekly doses of rituximab followed by observa-
fractory DLBCL. In that case, the role of AHCT is clear. tion or 2 years of maintenance therapy. After 4 weeks
of induction, ORR was 100% with CR of 67%. 5-year PFS
Unresolved dilemmas in treatment of NLPHL for the rituximab-only arm was 39% whereas for rituxi-
mab with maintenance it was 58.9% [26]. However, the
Early stages potential role of rituximab alone in induction treatment
Various treatment options have been evaluated in the early may be supported by the high rate of responses and no
stages. According to ESMO and NCCN, radiotherapy alone is severe grade 3/4 toxicity. Anti-CD20 antibodies can be
316 www.journals.viamedica.pl/acta_haematologica_polonicaEwa Paszkiewicz-Kozik, NLPH: recommendations and unresolved dilemmas
considered individually as induction treatment for early Another option is monotherapy with rituximab followed
stage NLPHL for patients in poor performance status with (or not) by two years of maintenance treatment. Prolonged
concomitant diseases. administration of rituximab may result in a longer PFS peri-
od compared to four doses of rituximab alone, but results
Advanced disease from the single small study were not statistically significant
There have been no randomized trials directly comparing [26]. Other preferences for refractory NLPHL are: radiother-
induction chemotherapy regimens, and the data is based apy alone for limited relapse, and systemic salvage chemo-
on retrospective observations or phase II trials. The upfront therapy with or without rituximab in advanced disease ac-
use of anti-CD20 antibody is strongly recommended due to cording to the guidelines for diffuse large B cell lymphomas.
the consistent expression of that antigen on the LP cells For young patients with a disseminated and refractory
surface. Therefore, the recommendation for ABVD alone (Acta Haematologica Polonica 2021, vol. 52, no. 4
histiocytes especially in variant histology pattern E [5]. cyte rich large B-cell lymphoma. Pathology. 2020; 52(1): 142–153,
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Author’scontributions 11. Cheson BD, Fisher RI, Barrington SF, et al. Alliance, Australasian
Leukaemia and Lymphoma Group, Eastern Cooperative Oncology
EP-K — sole author.
Group, European Mantle Cell Lymphoma Consortium, Italian Lym-
phoma Foundation, European Organisation for Research, Treatment
Conflict of interest of Cancer/Dutch Hemato-Oncology Group, Grupo Español de Médula
None. Ósea, German High-Grade Lymphoma Study Group, German Hod-
gkin’s Study Group, Japanese Lymphorra Study Group, Lymphoma
Financial support Study Association, NCIC Clinical Trials Group, Nordic Lymphoma Study
None. Group, Southwest Oncology Group, United Kingdom National Cancer
Research Institute. Recommendations for initial evaluation, staging,
Ethics and response assessment of Hodgkin and non-Hodgkin lymphoma:
The work described in this article has been carried out in the Lugano classification. J Clin Oncol. 2014; 32(27): 3059–3068,
accordance with The Code of Ethics of the World Medical doi: 10.1200/JCO.2013.54.8800, indexed in Pubmed: 25113753.
12. Eichenauer DA, Plütschow A, Fuchs M, et al. Long-term course of
Association (Declaration of Helsinki) for experiments involv-
patients with stage IA nodular lymphocyte-predominant Hodgkin lym-
ing humans; EU Directive 2010/63/EU for animal experi-
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ments; Uniform requirements for manuscripts submitted col. 2015; 33(26): 2857–2862, doi: 10.1200/JCO.2014.60.4363,
to biomedical journals. indexed in Pubmed: 26240235.
13. Biasoli I, Stamatoullas A, Meignin V, et al. Nodular, lymphocyte-pre-
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